1-Aryl-2-acylamido-3-fluoro-1-propanol acylates, methods for their manufacture and intermediates useful therein, methods for their use as antibacterial agents and compositions useful therefor

ABSTRACT

Described are D-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol esters and salts thereof, methods for their preparation, and methods for their use as antibacterial agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of my copending applicationU.S. Ser. No. 9,207 filed Feb. 5, 1979, now U.S. Pat. No. 4,235,892.

FIELD OF INVENTION

This invention relates to novel compositions-of-matter, to methods fortheir preparation, and to methods for their use as antibacterial agents.

More specifically, this invention relates to novel1-aryl-2-acylamido-3-fluoro-1-propanol antibacterial agents, to methodsfor their manufacture and to novel intermediates useful therein, topharmaceutical compositions comprising said1-aryl-2-acylamido-3-fluoro-1-propanols and to methods for their use intreating antibacterial infections.

In particular, this invention relates to D-(threo)-1-phenyl (or para-and/or meta-substituted-phenyl)-2-alkanoylamido (or2-halogenoalkanoylamido or 2-azidoalkanoylamido or2-methylsulfonylacetamido)-3-fluoro-1-propanol antibacterial agents,including the 3-fluoro-3-deoxy derivatives of chloramphenicol, of thedifluoroacetyl analog of chloramphenicol, of thiamphenicol,fluorthiamphenicol, tevenel, and fluortevenel (i.e., the difluoroacetylanalog of tevenel), and to 1-hydrocarboncarboxylate (preferably1-carboxyhydrocarboncarboxylate) esters and1-(aminohydrocarboncarboxylate) esters and their pharmaceuticallyacceptable salts, methods for their preparation and for their use asantibacterial agents.

PRIOR ART

Known in the art are broad spectrum antibiotics which may be classifiedas D-(threo)-1-p-substitutedphenyl-2-halogenoacetylamido-1,3-propanediols, including chloramphenicol(D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-1,3-propanediol),thiamphenicol(D-(threo)-1-p-methylsulfonylphenyl-2-dichloroacetamido-1,3-propanediol),fluorthiamphenicol(D-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-1,3-propanediol)and tevenel(D-(threo)-1-p-aminosulfonylphenyl-2-dichloroacetamido-1,3-propanediol).

Also known in the art is that any structural modification of the primaryhydroxyl group at C-3 of chloramphenicol, including replacement of thehydroxyl group by chlorine or bromine, destroys the biological activitythereof (F. E. Hahn, Antibiotics, Ed. Gottlieb and Shaw,Springer-Verlag, New York, (1967), p. 308; F. E. Hahn et al, Antibioticsand Chemotherapy, 6, No. 9, 531 (1956); L. Cima and A. Ilecto, IlFarmaco, Ed. Sc. 12, No. 6, 535 (1957); S. Mitsuhasi et al, Jap. J.Microbiol. 13, No. 2, 177-80 (1969); K. Megaim et al, Jap. J.Microbiology 15 (3), 219-27 (1971)).

Heretofore unknown in the art were derivatives ofD-(threo)-1-p-substituted-phenyl-2-halogenoalkanoylamido-1,3-propanediolsin which the 3-hydroxyl group was replaced by fluorine.

By my invention, I have developed methods for preparing novelD-(threo)-1-phenyl (or para and/or meta-substitutedphenyl)-2-alkanoylamido (or 2-halogenoalkanoylamido or2-azidoalkanoylamido or 2-methylsulfonylacetamido)-3-fluoro-1-propanolsand have found that, surprisingly, these 3-fluoro- derivatives are broadspectrum antibacterial agents useful in the treatment of gram positive,gram negative, and rickettsial infections. I have also discovered thatthe 3-fluoro-3-deoxy derivatives of chloramphenicol and of thiamphenicolare advantageously and unexpectedly cidal against bacteria resistant tochloramphenicol and thiamphenicol as well as against bacteria which aresusceptible to these parent antibiotics.

GENERAL DESCRIPTION OF THE INVENTION Composition-of-Matter Aspect

Included among the antibacterially active compositions-of-matter of thisinvention are D-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol acylatesof the following formula I: ##STR1## wherein R is a member selected fromthe group consisting of methyl or ethyl or a halogenated derivativethereof, dihalogenodeuteriomethyl, 1-halogeno-1-deuterioethyl,1,2-dihalogeno-1-deuterioethyl, azidomethyl and methylsulfonylmethyl;each of X and X' is a member selected from the group consisting of NO₂,SO₂ R₁, SOR₁, SR₁, SONH₂, SO₂ NH₂, SONHR₁, SO₂ NHR₁, COR₁, OR₁, R₁, CN,halogen, hydrogen, phenyl and phenyl substituted by halogen, NO₂, SO₂CH₃, R₁ or OR₁, wherein

R₁ is methyl, ethyl, n-propyl or isopropyl;

and Z is hydrogen or an acyl radical of a hydrocarboncarboxylic acid(preferably a hydrocarbondicarboxylic acid) having up to 16 carbon atomsor an acyl radical of an amino hydrocarboncarboxylic acid having up to12 carbon atoms; and the pharmaceutically acceptable salts of said acylradicals.

Included among the halogenated alkyl groups contemplated for the moietyR in this invention are the mono-, di- and tri-fluoro-, the mono-, di-and tri-chloro-, the mono- and di-bromo-, and the iodo-methyl groups aswell as the mono- and di-fluoro-, the mono- and di-chloro-, the mono-and di-bromo-, and the iodoethyl groups wherein the halogen substituentsare preferably on the carbon alpha to the carbonyl function. Alsoincluded are mixed diahlogenoalkyl groups in which both halogens arepreferably bonded to the carbon alpha to the carbonyl groups, e.g.,groups such as fluorochloro-, fluorobromo-, and chlorobromo-methyl andethyl, as well as trihalogenomethyl groups such as dichlorofluoro- anddifluorochloro-methyl. Additionally, among the halogenated alkyl group,R, are included those having a deuterio atom on the carbon alpha to thecarbonyl function, e.g., dihalogenodeuteriomethyl groups such asdichlorodeuterio-, difluorodeuterio- and chlorofluorodeuterio-methyl, aswell as 1-halogeno-1-deuterioethyl groups such as 1-fluoro-1-deuterio-and 1-chloro-1-deuterioethyl and 1,2-dihalogeno-1-deuterioethyl groupssuch as 1,2-dichloro-1-deuterio- and 1,2-difluoro-1-deuterio-ethyl.Thus, the 2-acylamido groups contemplated by this invention (i.e.,##STR2## include mono-, di-, and tri-halogeno-acetamido derivatives aswell as α-halogenopropionamido, β-halogenopropionamido-, and α,α- andα,β-dihalogenopropionamido derivatives and deuterio derivatives thereof.Of the foregoing, preferred are compounds of formula I wherein ##STR3##is dichloroacetamido, difluoroacetamido, fluorochloroacetamido, anddeuterio derivatives thereof.

Of the 1-phenyl derivatives of formula I contemplated by this invention,preferred are the p-substituted phenyl groups (i.e., compounds offormula I wherein X' is hydrogen), particularly the 1-p-nitrophenyl(i.e. X is NO₂), the 1-p-methylsulfonylphenyl (i.e. X is SO₂ CH₃), the1-p-aminosulfonylphenyl (i.e. X is SO₂ NH₂), and the1-p-methylsulfinylphenyl (i.e. X is SOCH₃).

The compounds of formula I have two assymetric centers at carbons 1 and2 of the propanol structure and, therefore, have four possiblestereoisomers. The preferred stereoisomer of my invention is the one inwhich the absolute configuration is D and the relative configuration isthreo. Thus, the compounds defined by formula I have the D-(threo)-configuration, which is the same isomeric form present in the prior artantibiotics chloramphenicol and the difluoroacetyl analog thereof,thiamphenicol, fluorthiamphenicol, and tevenel.

In addition to the foregoing, when R is a mixed diahlogenomethyl or a1-halogenoethyl or a deuterio derivative thereof, an assymetric centerexists within the acylamido group ##STR4## at the carbon to which thehalogen is bonded. It is to be understood that both stereoisomeric formswithin the acylamido group as well as racemates thereof are includedwithin the concept of my invention.

Of particular interest are compounds of formula I having a1-p-nitrophenyl or a 1-p-methylsulfonylphenyl group and a2-dichloroacetamido or a 2-difluoroacetamido or a2-(chlorofluoroacetamido) group or deuterio derivatives thereof, whichare the 3-fluoro-3-deoxy derivatives of chloramphenicol and thedifluoroacetyl analog thereof, thiamphenicol and fluorthiamphenicol, andof their corresponding 2-(chlorofluoroacetamido) derivatives thereof andof their deuterio derivatives. These areD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol (R=Cl₂CH; X=NO₂ ; X'=H); and its deuterio derivative (R=Cl₂ CD);D-(threo)-1-p-nitrophenyl-2-difluoroacetamido-3-fluoro-1-propanol (R=F₂CH; X=NO₂ ; X'=H) and its deuterio derivative (R=F₂ CD);D-(threo)-1-p-methulsulfonylphenyl-2-dichloroacetamido-3-fluoro-1-propanol(R=Cl₂ CH; X=SO₂ CH₃ ; X'=H) and its deuterio derivative (R=Cl₂ CD);D-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanol(R=F₂ CH; X=SO₂ CH₃ ; X'=H) and its deuterio derivative (R=Cl₂ CD); andthe 2-(chlorofluoroacetamido) analogs of the foregoing and theirdeuterio derivatives, e.g.,D-(threo)-1-p-nitrophenyl-2-(R,S-chlorofluoroacetamido)-3-fluoro-1-propanol(R=ClFCH; X =NO₂ ; X'=H) and its deuterio derivative (R=ClFCD). Theforegoing compounds advantageously have antibacterial activity againstorganisms resistant to, as well as against organisms susceptible to,their precursor 3-hydroxy antibiotics. Thus, these compounds are broadspectrum antibacterial agents having a broader spectrum of activity thanchloramphenicol or thiamphenicol, and are useful in the treatment ofgram positive, gram negative and rickettsial infections.

Other valuable broad spectrum antibacterial agents of formula I include:

D-(threo)-1-p-aminosulfonylphenyl-2-dichloroacetamido-3-fluoro-1-propanol(R is Cl₂ CH--; X is NH₂ SO₂ ; X' is H, a derivative of tevenel);

D-(threo)-1-p-aminosulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanol(R is F₂ CH--; X is NH₂ SO₂ ; X' is H, a derivative of fluortevenel);

D-(threo)-1-p-methylsulfinylphenyl-2-dichloroacetamido-3-fluoro-1-propanol(R=Cl₂ CH; X=SOCH₃ ; X'=H);

D-(threo)-1-p-methylsulfinylphenyl-2-difluoroacetamido-3-fluoro-1-propanol(R=F₂ CH; X=SOCH₃ ; X'=H);

D-(threo)-1-p-nitrophenyl-2-methylsulfonylacetamido-3-fluoro-1-propanol(R=CH₃ SO₂ CH₂ ; X=NO₂ ; X'=H); and

D-(threo)-1-p-nitrophenyl-2-azidoacetamido-3-fluoro-1-propanol (R=N₃ CH₂; X=NO₂ ; X'=H).

Also included among the antibacterially active compounds of thisinvention are the ester derivatives, e.g. 1-hydrocarboncarboxylates offormula I wherein Z is an acyl radical of a hydrocarboncarboxylic acidhaving up to 16 carbon atoms which may be saturated, unsaturated,straight chain or branched chain, aliphatic, cyclic, cyclic-aliphatic,aromatic, aryl-aliphatic, or alkyl-aromatic and may be substituted byhydroxy, alkoxy containing from 1 to 5 carbon atoms, carboxyl orhalogen. The 1-hydrocarboncarboxylates of theD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanols of my invention arethus derived from hydrocarboncarboxylic acids such as alkanoic acidsexemplified by formic, acetic, propionic, trimethylacetic, butyric,isobutyric, valeric, isovaleric, caproic, tert.-butylacetic, enanthic,caprylic, capric, cyclopentylpropionic, undecylic, lauric, palmitic, andadamantanecarboxylic acids; substituted alkanoic acids such asphenoxyacetic, trifluoroacetic, β-chloropropionic and pantothenic acids;aromatic and substituted aromatic acids including benzoic, toluic,p-chlorobenzoic, p-fluorobenzoic, p-methoxybenzoic, and3',5'-dimethylbenzoic acids; aryl-alkanoic acids such as phenylacetic,phenylpropionic, and β-benzoylaminoisobutyric acids; unsaturated acidssuch as acrylic, cinnamic, and sorbic acids; and, preferably, dibasicacids such as succinic, tartaric, and phthalic acids.

Other antibacterially active ester derivatives of formula I are thosewherein Z is an acyl radical of an amino acid containing up to 12 carbonatoms and which may be saturated, unsaturated, straight chain, branchedchain or cyclic, which may contain aromatic groups and which may besubstituted by hydroxyl groups. Amino acid ester derivatives of formulaI are thus compounds wherein Z is derived from a neutral amino acid suchas tryptophan, threonine, serine, hydroxyproline, proline, tyrosine,phenylalanine, isoleucine, leucine, valine, alanine, and, preferably,glycine. Amino acid ester derivatives of Formula I are also derived frombasic amino acids such as diaminobutyric acid, ornithine, and lysine.

Preferred ester derivatives of my invention include those derived fromdibasic hydrocarboncarboxylates, e.g. the 1-succinate and 1-palmitateesters, which provide water soluble, pharmaceutically acceptablecationic salts, e.g. the sodium or potassium salts, as well as saltswith an amine, e.g. trimethylamine. Also preferred are ester derivativesof amino acids which provide water soluble, pharmaceutically acceptableacid addition salts with mineral or organic acids, e.g. thehydrochloric, or sulfuric acid, or the succinic acid addition salts.

The term "pharmaceutically acceptable salts" of this invention thusincludes salts wherein the acidic hydrogen in the dibasichydrocarboncarboxylate esters of this invention is replaced with acation (e.g. sodiumD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylhemisuccinate) as well as salts wherein the acidic hydrogen forms anacid addition salt with an amine (e.g.D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylhemisuccinate N-trimethylamine salt). Also included in the term"pharmaceutically acceptable salts" are the acid addition salts formedbetween mineral or organic acids and the amine in the amino acid estersof this invention (e.g.D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylglycinate hydrochloride).

Among the pharmaceutically acceptable cationic salts of the dibasichydrocarboncarboxylate esters contemplated for this invention are saltsof alkali and alkaline earth metals (e.g. sodium, potassium, calcium,aluminum) and salts with an amine such as trialkylamines, procaine,dibenzylamine, N-benzyl-beta-phenethylamine,N,N'-dibenzylethylenediamine, N,N'-bisdehydroabietylethylenediamine,N-(lower)alkylpiperidines (e.g. N-ethylpiperidine), and N-methylglucamine.

The pharmaceutically acceptable cationic salts (e.g. the sodium salt ortrimethylamine salt) are prepared according to known procedures such asby combining equimolar quantities of the corresponding base (e.g. sodiumhydroxide or trimethylamine) to the dibasic hydrocarboncarboxylate esterderivative (e.g.D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylhemisuccinate)in an aqueous solution and lyophilizing the resultant solution of thedibasic hydrocarboncarboxylate salt (e.g. sodiumD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylhemisuccinate orD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylhemisuccinate trimethylamine salt).

The pharmaceutically acceptable acid addition salts of the 1-propylamino acid ester derivatives of this invention (e.g.D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylglycinate hydrochloride) are made according to known procedures such asby neutralizing the free base (e.g.D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylglycinate) with an appropriate acid (e.g. hydrochloric acid) to about pH5. Suitable acids for this purpose include acids such as hydrochloric,sulfuric, phosphoric, nitric, hydrobromic, acetic, propionic, maleic,ascorbic, citric and the like. A preferred amino acid ester, Z, isderived from an α-amino acid such as glycine. Preferred acid additionsalts of the glynate esters are the glycinate hydrochloride and sulfatesalt.

The physical embodiments of the pharmaceutically acceptable salts ofthis invention are characterized by being white or off-white solidswhich are soluble in water, sparingly soluble in most polar solvents,and insoluble in most non-polar organic solvents.

The D-(threo)-1-phenyl (and m and/or p-substitutedphenyl)-2-alkanoylamido (and halogenoalkanoylamido)-3-fluoro-1-propanolderivatives of this invention such as defined by formula I including thenon-toxic, pharmaceutically acceptable salts thereof, in general,exhibit broad spectrum antibacterial activity and possess improvedantibacterial activities compared to the parent antibiotics, i.e. to thecorresponding compounds containing a 3-hydroxyl function instead of a3-fluoro. This improved activity, particularly that of theD-(threo)-1-p-nitrophenyl- and the D-(threo)-1-p-methylsulfonylphenyl-derivatives is specifically manifest in the enhanced activity of theclaimed 3-fluoro compounds against organisms resistant to the precursor3-hydroxy compounds. Thus, for example, the compounds of this invention,as defined by formula I, particularly the D-(threo)-1-p-nitrophenyl- andD-(threo)-1-p-methylsulfonylphenyl-2-dichloroacetamido-3-fluoro-1-propanolsas well as the corresponding 2-difluoroacetamido and2-chlorofluoroacetamido analogs and deuterio derivatives thereof aremore active against organisms which inactivate the parent antibiotics byO-acetylation of the 3-hydroxy group or by O-acetylation of both the 1-and 3-hydroxyl groups. Additionally, the compounds of formula I are alsoactive against organisms which are sensitive to the parent organisms. Inbrief, the antibacterial compounds of formula I are active againstorganisms resistant to chloramphenicol and thiamphenicol while stillretaining activity against organisms sensitive to chloramphenicol.

Particularly useful compounds of my invention are those wherein R ishalogenomethyl, particularly dichloromethyl, difluoromethyl andchlorofluoromethyl and deuterio derivatives thereof, and wherein X' ishydrogen and X is aminosulfonyl, methylsulfinyl, and preferably nitro ormethylsulfonyl. Of these, a particularly valuable group are theD-(threo)-1-p-nitrophenyl- and the D-(threo)-1-p-methylsulfonylphenylderivatives of formula I, particularly the 2-dichloroacetamido-,2-difluoroacetamido, and 2-chlorofluoroacetamido derivatives thereof andtheir deuterio derivative, which are broad spectrum antibiotics, beingactive against gram positive bacteria (e.g. Staphylococcus aureus) andgram negative bacteria (e.g. Escherichia coli, Hemophilus influenzae,Klebsiella, Salmonella, Shigella, Proteus, Enterobacter, and Serratia)as determined by standard dilution tests, including bacteria resistantto the 3-hydroxy analog precursor antibiotics, chloramphenicol andthiamphenicol and their 2-difluoroacetamido and 2-chlorofluoroacetamidocounterparts including their deuterio derivatives.

Particularly useful antibacterials of this invention areD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol;D-(threo)-1-p-nitrophenyl-2-difluoroacetamido-3-fluoro-1-propanol;D-(threo)-1-p-methylsulfonylphenyl-2-dichloroacetamido-3-fluoro-1-propanol;andD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanol,the corresponding 2-(R,S-chlorofluoroacetamido) derivatives thereof andthe corresponding 2-(dihalogenodeuterioacetamido) derivatives of theforegoing.

Particularly useful ester derivatives of the compounds of the inventionare the hemisuccinate esters particularly in the form of the sodium andtrimethylamine cationic salts, and the glycinate ester particularly inthe form of its hydrochloride or sulfate acid addition salt. Asspecifically preferred ester derivatives, there may be mentioned thesodium and trimethylamine salts ofD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylhemisuccinate and the hydrochloride and sulfate acid addition salts ofD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylglycinate. The pharmaceutically acceptable salts of the specifiedcompounds of the general formula I, such as the aforementioned salts,are usually white or off-white solids which are generally soluble inwater, sparingly soluble in polar solvents and insoluble in non-polarsolvents.

Another composition-of-matter aspect of my invention areD-(threo)-1-aryl-2-amino-3-fluoro-1-propanols of formula II: ##STR5##wherein X and X' are as defined for formula I and R₂ and R₃ are hydrogenor together form an amino protecting group.

The amino protecting groups (R₂ and R₃ together) contemplated for thecompounds of formula II are preferably imido derivatives of dicarboxylicacids such as succinimido and, preferably, phthalimido.

The compounds of formula II are valuable as intermediates in preparingthe antibacterially active compounds of formula I disclosed hereinaboveas described in the process aspect of this invention disclosedhereinbelow.

PROCESS ASPECT OF THE INVENTION

The process aspect of this invention resides in the concept of theprocess for the preparation of aD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol of formula I whichcomprises the reaction ofD-(threo)-1-aryl-2-N-protected-amino-1,3-propanediol with dialkylaminesulfur trifluoride in an inert organic solvent followed by removal ofthe N-protecting group in the thereby formedD-(threo)-1-aryl-2-N-protected-amino-3-fluoro-1-propanol; thencereaction of the resulting D-(threo)-1-aryl-2-amino-3-fluoro-1-propanolwith a lower alkanoic acid derivative such as alkanoic acid chloride oranhydride in the presence of a base and, in the case of theα,α-dihalogeno alkanoic acids, even with a lower alkyl ester in a loweralkanol.

The D-(threo)-1-aryl-2-amino-1,3-propanediol, precursors for theN-protected starting compounds of this process, are either knowncompounds or are conveniently prepared according to known procedures.Thus, for example,D-(threo)-1-p-methylsulfonylphenyl-2-amino-1,3-propanediol isconveniently prepared via acid hydrolysis of thiamphenicol (i.e.D-(threo)-1-p-methylsulfonylphenyl-2-dichloroacetamido-1,3-propanediol.

The 2-N-protected amino starting compound of my process preparedaccording to procedures well known in the art.

In the first step of my process, wherein the primary 3-hydroxyl-function in a D-(threo)-1-aryl-2-N-protected amino-1,3-propanediol isfirst selectively replaced by fluorine, the fluorinating agent of choiceis a dialkylamine sulfur trifluoride, preferably diethylamine sulfurtrifluoride. Other fluorinating agents which may be used in my processare sulfur trifluoride morpholine, sulfur trifluoride piperidine andother stable sulfur trifluoride-secondary amine adducts.

This step is conveniently carried out at temperatures in the range of-10° to +50° C., preferably at 0° C. in an inert organic solvent. By"inert organic solvent" is meant any organic or inorganic solvent inwhich the D-(threo)-1-aryl-2-protected amino-1,3-propanediol startingcompounds and the reagents are reasonably soluble, and which will notinterfere with the process under the reaction conditions thereof sothere are produced a minimum of competing side reactions. The first stepof our process is preferably carried out in an aprotic solvent, e.g.tetrahydrofuran, dioxane, or tetrahydropyran.

After removal of the N-protecting group utilizing known techniques (suchas removal of a phthalimido group with hydrazine hydrate) the secondstep of my process comprises converting the unprotected 2-amino functionto a 2-alkanoylamido function by reaction thereof with a lower alkanoicacid derivative selected from acetic acid anhydride or chloride, orpropionic acid anhydride or chloride in the presence of base, or, in thecase of halogeno acetic acids or halogeno propionic acids, with a loweralkyl ester of said halogeno alkanoic acids in a lower alkanol (e.g. analkanol having up to 4 carbon atoms) said alkanoic acid derivativesbeing known compounds or conveniently prepared by known techniques.

Compounds of formula I wherein R is a halogenodeuterioalkyl are preparedfrom the corresponding compound of formula I wherein R is halogenoalkylutilizing conventional deuterium exchange reactions, e.g., utilizingmethyl alcohol-D (i.e. CH₃ OD).

A preferred species of my process is that whereby aD-(threo)-1-aryl-2-amino-1,3-propanediol is first converted to thecorresponding 2-N-protected derivative and then to the corresponding1-aryl-2-N-protected-amino-3-fluoro-1-propanol by replacement of theprimary 3-hydroxyl with fluorine, after which the 2-amino function isliberated and then converted to a 2-acetamido or 2-propionamido functionor to halogeno derivatives thereof, i.e. aD-(threo)-1-aryl-2-N-substituted amino-3-fluoro-1-propanol. Thus,D-(threo)-1-p-nitrophenyl-2-phthalimido-1,3-propanediol is dissolved inan aprotic solvent (e.g. tetrahydrofuran) and reacted with an equimolarquantity of a dialkylamine sulfur trifluoride (e.g. diethylamine sulfurtrifluoride) at temperatures in the range of from about 0° C. to roomtemperatures whereby is prepared a 3-fluoro-1-propanol derivative (e.g.D-(threo)-1-p-nitrophenyl-2-phthalimido-3-fluoro-1-propanol) which isconveniently isolated and purified utilizing conventional techniques,usually chromatographic methods. Removal of the N-protecting group (e.g.phthalimido) is then effected via known techniques (e.g. hydrazinehydrate in ethanol) and the resultingD-(threo)-1-aryl-2-amino-3-fluoro-1 -propanol (e.g.D-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol) is converted tothe corresponding 2-acetylamido derivative (e.g. 2-dichloroacetamido),by reaction with a halogeno alkanoic acid alkyl ester in an alkanol(e.g. methyl dichloroacetate in methanol) at elevated temperatures(usually at about 60° to 100° C.). Isolation and purification of theD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol of formula I is thenconveniently isolated by removing the solvents and treating the residueto extraction and chromatographic and crystallization methods.

Alternatively, the D-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanols offormula I are prepared from the corresponding 3-oxazolidine of followingformula III with hydrogen fluoride in the presence of fluoride ion, e.g.in the presence of lithium fluoride: ##STR6## wherein X, X' and R are asdefined for formula I.

The oxazolidines of formula III may be prepared according to knownmethods. Alternatively, the oxazolidines are prepared by reacting aD-(threo)-1-aryl-2-acylamido-1,3-propanediol (e.g. chloramphenicol) witheither trifluoromethylsulfonyl chloride in pyridine or p-toluenesulfonylchloride in pyridine. In the latter case, the initial product is the3-p-toluenesulfonate ester which cyclizes to the oxazolidine structureupon treatment with a base in a solvent.

Another method of preparing compounds of formula I comprises utilizing astarting material differing from the desired product in having in one orboth of the para- and meta- positions of the phenyl moiety a substituentX" which is a precursor of X or X' and thence converting X" into thedesired value of X or X'. For example, compounds of formula I wherein X'is hydrogen and X is --SOR₁ or --SO₂ R₁ may be obtained by oxidation ofthe corresponding compound (which contains instead of the X substituentanother substituent, X", which is --SR₁ and SOR₁, respectively),utilizing oxidizing agents and conditions commonly employed in theconversion of an aryl thio-ether group into sulfinyl, e.g., utilizingsodium metaperiodate, or for the conversion of an aryl sulfinyl groupinto sulfonyl.

Compounds of formula I wherein Z is an acyl radical are preferablyprepared by appropriate esterification of the corresponding compound offormula I in which Z is hydrogen, the so-obtained ester being isolatedas such or where appropriate in the form of a pharmaceuticallyacceptable salt.

PHARMACEUTICAL COMPOSITION AND METHOD-OF-USE Aspects of the Invention

The present invention includes within its scope the concept of apharmaceutical composition comprising aD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol of formula I togetherwith a compatible, pharmaceutically acceptable carrier or coating.

Also included within this invention is the concept of the method ofeliciting an antibacterial response in a warm-blooded animal having asusceptible bacterial infection which comprises administering to saidanimal a non-toxic, antibacterially effective amount of aD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol of formula I.

As discussed hereinabove, theD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanols of formula I are broadspectrum antibacterial agents which, advantageously, exhibit activityagainst organisms which are resistant to their 3-hydroxy precursors.Thus, the compounds of this invention can be used alone or incombination with other antibiotic agents to prevent the growth or reducethe number of bacteria in various environments. They may be used, forexample, to disinfect laboratory glassware, dental and medical equipmentcontaminated with Staphylococcus aureus or other bacteria inhibited bythe 3-fluoro-1-propanols of this invention. The activity of theD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanols renders them usefulfor combatting infections caused by gram negative organisms, e.g.species of Proteus and Salmonella or by gram positive organisms, e.g.Staphylococcus aureus, and by Ricksettial organisms.

In general, the dosage ofD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol will be dependent onthe age and weight of animal species being treated, the mode ofadministration, and the type and severity of bacterial infection beingprevented or reduced. In general, the dosage ofD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol employed to combat agiven infection will be similar to the dosage requirements of thecorresponding 3-hydroxy analog or of chloramphenicol. Additionally, theD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanols of formula I, e.g.D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol andthe corresponding 1-p-methylsulfonylphenyl compound, are alsoadvantageously cidal against certain organisms which are resistant tothe corresponding 3-hydroxy precursor, i.e. which are resistant tochloramphenicol and to thiamphenicol.

The D-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanols of formula I andthe pharmaceutically acceptable salts of esters thereof may beadministered parenterally, orally and topically.

The antibacterials of this invention may be utilized in liquid form suchas solutions, suspensions, and the like for otic and optic use and mayalso be administered parenterally via intramuscular injection. Theinjectable solution or suspension will usually be administered at fromabout 1 mg. to about 15 mgs. of antibacterial per kilograms of bodyweight per day divided into about 2 to about 4 doses. The precise dosedepends on the stage and severity of the infection, the susceptibilityof the infecting organism to the antibacterial and the individualcharacteristics of the animal species being treated.

For oral administration, theD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol antibacterials may becompounded in the form of tablets, capsules, elixirs or the like or mayeven be admixed with animal feed. It is in these dosage forms that theantibacterials are most effective for treating bacterial infections ofthe gastrointestinal tract which infections cause diarrhea.

The D-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanols may also beapplied topically in the form of ointments, both hydrophilic andhydrophobic, in the form of lotions which may be aqueous, non-aqueous orof the emulsion type or in the form of creams. Pharmaceutical carriersuseful in the preparation of such formulations will included, forexample, such substances as water, oils, greases, polyesters, polyolsand the like.

In general, the topical preparations will contain from about 0.1 toabout 3 gms. of D-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol offormula I per 100 gms. of ointment, cream or lotion. The topicalpreparations are usually applied gently to lesions from about 2 to 5times a day.

FORMULATIONS

The following formulations are to exemplify some of the dosage forms inwhich the antibacterial agents of this invention may be employed. Ineach, the active ingredient is designated by the term "Drug" which ismeant to indicate one of the following compounds.

D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol;D-(threo)-1-p-methylsulfonylphenyl-2-dichloroacetamido-3-fluoro-1-propanol;andD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanol.It will be appreciated, however, that each of these compounds may bereplaced by equally effective quantities of other compounds defined byformula I.

    ______________________________________                                        Formulation 1                                                                 Oral Suspension                                                                                       mg/ml                                                 ______________________________________                                        Drug, Micronized          20.0                                                Sorbitol solution, USP    250.0                                               Methylparaben, USP        0.5                                                 Propylparaben, USP        0.1                                                 Propylene Glycol, USP     50.0                                                Veegum HU (Mg-Aluminum Silicate)                                                                        10.0                                                Sodium Carboxymethylcellulose                                                                           5.0                                                 Pluronic F-68             0.2                                                 Flavor (sufficient)                                                           Purified Water, USP qs ad 1 ml                                                ______________________________________                                    

MANUFACTURING PROCEDURE

Disperse the Veegum and Sodium carboxymethylcellulose in hot water (80°C.). Add the Sorbitol solution with stirring, followed by the micronizeddrug. Add the Pluronic F-68 previously dissolved in a portion of hotwater (80° C.). Cool the batch to 30° C. Dissolve the Methyl andPropylparaben in the Propylene Glycol. Add the solution to the batch.Add the flavors to the batch. Mix until homogenous.

    ______________________________________                                        Formulation 2                                                                 Ointment                                                                                        mg/g                                                        ______________________________________                                        Drug, Micronized    20.0                                                      Mineral Oil, USP    50.0                                                      White Petrolatum, USP qs ad                                                                       1.0 of g.                                                 ______________________________________                                    

MANUFACTURING PROCEDURE

Heat the weighed quantity of White Petrolatum and Mineral Oil to 65° andmix until uniform. Cool mixture to 50°-55° C. with stirring. The drugwhich has been dispersed in a portion of the Mineral Oil and milled, isadded to the remainder of the base with stirring. The ointment is cooledto room temperature.

    ______________________________________                                        Formulation 3                                                                 Cream                                                                                            mg/g                                                       ______________________________________                                        Drug, Micronized     20.0                                                     White Petrolatum, USP                                                                              150.0                                                    Mineral Oil, USP     50.0                                                     Cetomacrogol 1000    22.0                                                     Cetyl Alcohol        40.0                                                     Stearyl Alcohol, USP 40.0                                                     Sodium Phosphate, Monobasic                                                                         4.0                                                     Propylene Glycol, USP                                                                              50.0                                                     Purified Water qs ad 1 g                                                      ______________________________________                                    

MANUFACTURING PROCEDURE

Dissolve the Propylene Glycol and Monobasic Sodium Phosphate in aspecified amount of Purified water at 80°-90° C. A weighed quantity ofWhite Petrolatum, Cetomacrogol 1000, Cetyl Alcohol and Stearyl Alcoholare heated to 70°-75° C., and uniformly mixed. The melted waxes areadded to the aqueous portion with stirring while cooling to 45°-50° C.The drug is slurried in a portion of Cetamacrogol dissolved in aspecified amount of water. The active slurry is milled, then added tothe formula while stirring. The cream is cooled to room temperature.

    ______________________________________                                        Formulation 4                                                                 Lotion                                                                                         mg/g                                                         ______________________________________                                        Drug                20.0                                                      Propylene Glycol, USP                                                                            350.0                                                      Alcohol, USP       350.0                                                      Hydroxypropylcellulose                                                                            2.5                                                       Purified Water qs ad                                                                             1 g                                                        ______________________________________                                    

MANUFACTURING PROCEDURE

Dissolve the drug in Propylene Glycol heated to 50°-60° C. Cool to30°-35° C. Add the Alcohol and Purified Water with stirring. Dispersethe Hydroxypropylcellulose with stirring. Cool to room temperature.

    ______________________________________                                        Formulation 5                                                                 Injectable Solution                                                                             mg/ml                                                       ______________________________________                                        Drug                250.0                                                     Sodium Tartrate     1.0                                                       Tartaric Acid       4.0                                                       N,N-dimethylacetamide                                                                             500.0                                                     Water for Injection qs ad                                                                         1.0 ml                                                    ______________________________________                                    

MANUFACTURING PROCEDURE

Dissolve Sodium Tartrate and Tartaric Acid in a portion of Water forInjection. Dissolve the drug in N,N-dimethylacetamide. Mix bothsolutions and bring it to the final volume with Water for Injection.Aseptically filter the solution through a sterile 0.22 μm teflon(Millipore) membrane.

FORMULATION 6 Sterile Powder

For reconstitution with Water for Injection or normal saline to givefinal concentration of 100 mg/ml of drug in the solution intended forparenteral use.

    ______________________________________                                        Drug (lyophilized)      1.0 g                                                 ______________________________________                                    

MANUFACTURING PROCEDURE

Make a suitable slurry of the drug with Water for Injection andlyophilize it.

    ______________________________________                                        Formulation 7                                                                 Capsules                                                                      Item Ingredient   mg/cap   mg/cap   mg/cap                                    ______________________________________                                        1.  Drug              25       50     250                                     2.  Lactose Impalpable Powder                                                                       222      197    185                                     3.  Corn Starch       50       50     60                                      4.  Magnesium Stearate                                                                              3.0      3.0    5.0                                         TOTAL             300 mg   300 mg 500 mg                                  ______________________________________                                    

MANUFACTURING PROCEDURE

Mix Item Nos. 1, 2 and 3 in a suitable mixer. Using a suitable mill,pass the mixture through a No. 40 screen. Add Item No. 4 and mix for 3-5minutes. Encapsulate the mixture in two-piece hard gelatin capsules,using a suitable capsulating machine.

    ______________________________________                                        Formulation 8                                                                 Tablets                                                                                            mg/     mg/     mg/                                      Item Ingredient      Tab.    Tab.    Tab.                                     ______________________________________                                        1.  Drug, Micronized     25      50    250                                    2.  Lactose, Impalpable Powder                                                                         202.0   177.0 234                                    3.  Microcrystalline Cellulose                                                                         30.0    30.0  60.0                                   4.  Corn Starch (10% paste in Water)                                                                   10.0    10.0  20.0                                   5.  Corn Starch          30.0    30.0  30.0                                   6.  Magnesium Stearate   3.0     3.0   6.0                                        TOTAL                300 mg. 300 mg.                                                                             600 mg.                                ______________________________________                                    

MANUFACTURING PROCEDURE

Mix Item Nos. 1, 2 and 3 in a suitable blender. Add Item No. 4 and mixuntil a damp mass is formed. Using a suitable mill, pass the damp massthrough a coarse sieve (e.g. No. 6) to yield the granules. Dry thegranules for 8-16 hours at 40°-50° C. Mill the dried granules using asuitable mill through a No. 20 sieve. Add Item No. 5 to the milledgranules and mix for 5 to 10 minutes. Mix further for 3-5 minutes afterthe addition of Item No. 6. Compress the mixture into a tablet using asuitable tablet press.

The processes described hereinabove are illustrated in detailhereinbelow in the Preparations and Examples which should not beconstrued as limiting the scope of my invention, equivalents of thespecific disclosure herein will be obvious to those skilled in the artand are contemplated as included within the concept of my invention.

EXAMPLE 1D-(THREO)-1-p-NITROPHENYL-2-DICHLOROACETAMIDO-3-FLUORO-1-PROPANOL

A. D-(Threo)-1-p-Nitrophenyl-2-Phthalimido-1,3-Propanediol

Add D-(threo)-1-p-nitrophenyl-2-amino-1,3-propanediol (21.2 gms., 0.1mole), triethylamine (15 ml.) and phthalic anhydride (14.8 gms., 0.1mole) to toluene (600 ml.) in a flask equipped with an overhead stirrerand a Dean-Stark water collector. Stir the reaction mixture at refluxtemperature for 4 hours, cool with stirring to about 50° C., then addethanol (300 ml.). Stir at room temperature for 1 hour, then allow thereaction mixture to remain at room temperature for 18 hours. Separatethe resultant white precipitate by filtration, wash the filtrate withethanol and dry to obtainD-(threo)-1-p-nitrophenyl-2-phthalimido-1,3-propanediol, yield 28.4 gms.(83% theory); m.p. 228°-229° C. (decomp.). Mass Spectrum: (M⁺ +1) 343;pmr: (dmso-d₆): δ6.93-8.33 (aromatic hydrogens); 5.93 (d, J=4.0 Hz,benzylic OH); 5.27 (M, H-1); 4.83 (broad t, primary OH); 3.77-4.62 (m,CH₂ ); 3.5 (m, H-2).

B. D-(Threo)-1p-Nitrophenyl-2-Phthalimido-3-Fluoro-1-Propanol

To a stirring solution ofD-(threo)-1p-nitrophenyl-2-phthalimido-1,3-propanediol (42.76 gms.,0.125 moles) in dry tetrahydrofuran (800 ml.) maintained at 0° C., adddropwise diethylaminosulfurtrifluoride (17.5 ml.). Stir the reactionmixture at 0° C. for 30 minutes, then allow the reaction mixture to warmto room temperature and stir at room temperature for an additional 5hours. Evaporate the tetrahydrofuran in vacuo and chromatograph theresultant residue on a column of silica gel (2 kg.) eluting with amixture of chloroform: ethanol (99:1). Combine the homogenous eluatescontaining the desired product as determined by thin layerchromatography and evaporate in vacuo to a residue ofD-(threo)-1-p-nitrophenyl-2-phthalimido-3-fluoro-1-propanol, yield 32gms. (74.4% theory). Further purify by crystallization from ethylacetate: petroleum ether; m.p. 188°-190° C.; [α]_(D) ²⁶ -55.6° (c, 1 indimethylformamide); Mass Spectrum: (M⁺ +1) 345; M⁺ 344; pmr:(dmso-d₆):δ7.70-8.42 (aromatic hydrogens); 6.20 (d, J=4.0 Hz, benzylicOH); 5.3 (m, H-1); 4.1-4.95 (m, CH₂ F, H-2); Analysis Calculated for:C₁₇ H₁₃ N₂ O₅ F: C, 59.29; H, 3.80; N, 8.13; F, 5.52%. Found: C, 59.17;H, 3.93; N, 7.80; F, 5.40%.

C. D-(Threo)-1-p-Nitrophenyl-2-Amino-3-Fluoro-1-Propanol

Heat a mixture ofD-(threo)-1-p-nitrophenyl-2-phthalimido-3fluoro-1-propanol (25.8 gms., 5mmols), hydrazine hydrate (99%, 4 gms., 80 mmols), and ethanol (460 ml.)at reflux temperature for 4 hours, then let the reaction mixture standat room temperature for 18 hours. Separate the solids by filtration andwash with a little ethanol. Concentrate the combined filtrate andethanol washings in vacuo and extract the resultant residue with achloroform: ethanol mixture (90:10) (700 ml.). Combine the chloroform:ethanol extracts and evaporate in vacuo to 18.1 g. of a residuecomprising D-(threo)-1p-nitrophenyl-2-amino-3-fluoro-1-propanol, whichcan be used without further purification in the procedure described inthe following example.

To prepare an analytical sample, chromatograph the foregoing residue onsilica gel eluting with chloroform: methanol: ammonium hydroxide(30:5:0.1). Combine the like fractions containing the desired product asdetermined by thin layer chromatography and evaporate the combinedeluates to a residue comprisingD-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol; m.p. 145°-147°C.; [α]_(D) ²⁶ -59° (c, 0.3 in dimethylformamide). Mass Spectrum: (M⁺+1) 215, pmr; (dmso-d₆); δ 7.42-8.30 (aromatic hydrogens); 4.78 (d,J=4.0 Hz, H-1); 3.8-4.78 (m, CH₂); 2.8-3.3 (m, H-2). Analysis Calculatedfor: C₉ H₁₁ N₂ O₃ F: C, 50.47; H, 5.18; N, 13.08%. Found: C, 50.86; H,5.53; N, 12.70%.

D. D-(Threo)-1-PNitrophenyl-2-Dichloroacetamido-3-Fluoro-1-Propanol

To D-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol prepared asdescribed in Example 1C (18.1 gms.) add 80 ml. of a solution containingmethyl dichloroacetate and 7 ml. of methanol. Heat the reaction mixtureat 100° C. for 4 hours. Monitor the progress of the reaction by thinlayer chromtography adding about 1 ml. of triethylamine as the reactionproceeds slowly. Remove the solvents in vacuo and wash the resultantresidue with petroleum ether (200 ml.). Dissolve the washed residue inchloroform (about 700 ml.), concentrate in vacuo, and chromatograph theresultant residue on a column of silica gel (2 kg.) eluting withchloroform: ethanol (98:2). Pour the like fractions containing thedesired product as determined by thin layer chromatography and evaporatethe combined fractions in vacuo to a residue comprisingD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol, yield19.9 gms. (81.5% theory). Further purify by dissolving the residue inchloroform (200 ml.) (concentrating to a volume of about 100 ml.) andadding petroleum ether (about 300 ml.). Separate the resultantprecipitate by filtration to obtain purifiedD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol, yield16.6 gms.; m.p. 103°-104° C.; [α]_(D) ²⁶ -23.4° (c, 0.3 indimethylformamide). Mass Spectrum: M⁺ 325: pmr: (dmso-d₆), δ 8.62 (d,J=9.0 Hz, NH); 7.54-8.30 (aromatic hydrogens); 6.5 (s, CHCl₂); 6.2 (d,J=4.0 Hz, benzylic OH); 4.0-5.2 (m, CH₂ F, H-1 and H-2); AnalysisCalculated for: C₁₁ H₁₁ N₂ O₄ FCl₂ : C, 40.64; H, 3.41; N, 8.62; Cl,21.81; F, 5.84%. Found, C, 41.22; H, 3.74; N, 8.51; Cl, 21.06; F, 6.07%.

EXAMPLE 2D-(THREO)-1-p-Nitrophenyl-2-Difluoroacetamido-3-Fluoro-1-Propanol

To D-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol (0.428 gms., 2mmol) add ethanol (5 ml.) ethyl difluoroacetate (0.5 gms.). Heat thereaction mixture at reflux temperature for 2 hours, then remove thesolvent in vacuo and chromatograph the resultant residue on silica gel(50 gms.) eluting with chloroform:ethanol (95:5). Combine the likefractions containing the desired product as determined by thin layerchromatography and evaporate the combined fractions in vacuo to aresidue (0.47 g.) comprisingD-(threo)-1-p-nitrophenyl-2-difluoroacetamido-3-fluoro-1-propanol, yield80% theory; m.p. 97°-98° C.; Mass Spectrum: (M⁺ +1), 293; pmr:(dmso-d₆); δ 8.8 (d, J=8.0 Hz, NH), 7.49-8.32 (aromatic hydrogens); 6.12(t, J=54.0 Hz, CHF₂); 6.10 (d, J=4.0 Hz, benzylic OH); 4.05-5.05 (m, CH₂F, H-1 and H-2).

EXAMPLE 3D-(Threo)-1-p-Nitrophenyl-2-Trifluoroacetamido-3-Fluoro-1-Propanol

In a manner similar to that described in Example 2, treatD-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol in ethanol withethyl trifluoroacetate. Isolated and purify the resultant products in amanner similar to that to obtainD-(threo)-1-p-nitrophenyl-2-trifluoroacetamido-3-fluoro-1-propanol; m.p.123°-124° C.; Mass Spectrum: m/e 152 ##STR7## 158 (F₃ CCONH═CHCH₂ F).pmr: (dmso-d₆); δ 9.5 (d, J=9.0 Hz, NH); 7.5-8.3 (aromatic hydrogen);6.1 (d, J=4.0 Hz, benzylic OH); 4.1-5.3 (m, CH₂, H-1 and H-2).

EXAMPLE 4 D-(Threo)-1-p-Nitrophenyl-2-Acetamido-3-Fluoro-1-Propanol

Method A

To D-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol (0.428 g, 2mmol), add ethanol (5 ml.) and with stirring add acetic anhydride (0.3g, 3 mmol.). After 30 minutes at room temperature, remove the solventsin vacuo and chromatograph the residue and isolate the product in amanner similar to that described in Example 2 to obtainD-(threo)-1-p-nitrophenyl-2-acetamido-3-fluoro-1-propanol.

Method B

To D-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol (0.428 g., 2mmol.), add ethanol (5 ml.) and triethylamine (0.202 g., 2 mmol.). Coolthe solution to 5° C. with stirring and then add, dropwise, acetylchloride (0.157 g., 2 mmol.). After 30 minutes at room temperature,isolate and purify the resultant product in a manner similar to thatdescribed in method A to obtain the title compound.

EXAMPLE 5 OtherD-(Threo)-1-p-Nitrophenyl-2-Acylamido-3-Fluoro-1-Propanols

A. 2-Polyhalogenoacetamido and 2-α,α-DihalogenopropionylamidoDerivatives

In a manner similar to that described in Example 2, treatD-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol in methanol orethanol with each of the following acetic acid or propionic acid esters:

(1) Methyl trichloroacetate,

(2) Methyl dibromoacetate,

(3) Methyl dichlorofluoroacetate,

(4) Methyl α,α-difluoropropionate,

(5) Methyl α,α-dichloropropionate,

(6) Methyl chlorodifluoroacetate.

Isolate and purify each of the resulting products in a manner similar tothat described in Example 2 to obtain, respectively,

(1) D-(threo)-1-p-nitrophenyl-2-trichloroacetamido-3-fluoro-1-propanol,

(2) D-(threo)-1-p-nitrophenyl-2-dibromoacetamido-3-fluoro-1-propanol,

(3)D-(threo)-1-p-nitrophenyl-2-dichlorofluoroacetamido-3-fluoro-1-propanol,

(4)D-(threo)-1-p-nitrophenyl-2-α,α-difluoropropionamido-3-fluoro-1-propanol,

(5)D-(threo)-1-p-nitrophenyl-2-α,α-dichloropropionamide-3-fluoro-1-propanol,

(6)D-(threo)-1-p-nitrophenyl-2-dichlorofluoroacetamido-3-fluoro-1-propanol.

B. 2-Monohalogenoalkanoylamido and 2-α,β-DihalogenopropionoylamidoDerivatives

In a manner similar to that described in Example 4 (method B), treatD-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol in methanol orethanol with each of the following acetic acid or propionic acidchlorides:

(7) Fluoroacetyl chloride,

(8) Chloroacetyl chloride,

(9) Bromoacetyl chloride,

(10) Iodoacetyl chloride,

(11) Propionyl chloride,

(12) α-Fluoropropionyl chloride,

(13) α-Chloropropionyl chloride,

(14) α-Bromopropionyl chloride,

(15) α-Iodopropionyl chloride,

(16) β-Chloropropionyl chloride,

(17) β-Bromopropionyl chloride,

(18) β-Iodopropionyl chloride,

(19) α,β-Dichloropropionyl chloride,

(20) α,β-Difluoropropionyl chloride,

Isolate and purify each of the resulting products in a manner similar tothat described in Example 2 to obtain, respectively,

(7) D-(threo)-1-p-nitrophenyl-2-fluoroacetamido-3-fluoro-1-propanol,

(8) D-(threo)-1-p-nitrophenyl-2-chloroacetamido-3-fluoro-1-propanol,

(9) D-(threo)-1-p-nitrophenyl-2-bromoacetamido-3-fluoro-1-propanol,

(10) D-(threo)-1-p-nitrophenyl-2-Iodoacetamido-3-fuoro-1-propanol,

(11) D-(threo)-1-p-nitrophenyl-2-propionamido-3-fluoro-1-propanol,

(12)D-(threo)-1-p-nitrophenyl-2-α-fluoropropionamido-3-fluoro-1-propanol

(13)D-(threo)-1-p-nitrophenyl-2-α-chloropropionamido-3-fluoro-1-propanol

(14)D-(threo)-1-p-nitrophenyl-2-α-bromopropionamido-3-fluoro-1-propanol,

(15) D-(threo)-1-p-nitrophenyl-2-α-iodopropionamido-3-fluoro-1-propanol,

(16)D-(threo)-1-p-nitrophenyl-2-β-chloropropionamido-3-fluoro-1-propanol

(17)D-(threo)-1-p-nitrophenyl-2-β-bromopropionamido-3-fluoro-1-propanol,

(18) D-(threo)-1-p-nitrophenyl-2-β-iodopropionamido-3-fluoro-1-propanol,

(19)D-(threo)-1-p-nitrophenyl-2-α,β-dichloropropionamido-3-fluoro-1-propanol,

(20)D-(threo)-1-p-nitrophenyl-2-α,β-difluoropropionamido-3-fluoro-1-propanol.

EXAMPLE 6D-(Threo)-1-p-Methylsulfonylphenyl-2-Dichloroacetamido-3-Fluoro-1-Propanol

A. D-(Threo)-1 -p-Methylsulfonylphenyl-2-Phthalimido-1,3-Propanediol

Suspend thiamphenicol (71 gms., 200 mmols) in water (300 ml.) containingconcentrated hydrochloric acid (25 ml.). Stir the reaction mixture atreflux temperature for 6 hours, then evaporate to dryness in vacuo. Addtoluene (100 ml.) to the resultant residue and evaporate. Repeat thisprocedure again and dry the residue comprising1-p-methylsulfonylphenyl-2-amino-1,3-propanediol hydrochloride. Stir theforegoing dried residue in toluene (1400 ml.), then add with stirringtriethylamine (29.9 gms.) and phthalic anhydride (44 gms.). Heat thereaction mixture at reflux temperature for 6 hours using a Dean-Starkwater remover. Cool the reaction mixture, evaporate the solvent invacuo, then dissolve the resultant residue in ethyl acetate (1.5liters), wash the ethyl acetate solution with 1 N hydrochloric acid (800ml.), then extract the hydrochloric acid washes twice with ethyl acetate(500 ml.), then combine the ethyl acetate solution with the originalorganic solution. Dry the combined ethyl acetate solutions over sodiumsulfate and evaporate to dryness. Stir the resultant residue in ethanol(300 ml.), then set aside for 2 hours. Separate the resulting solid byfiltration, wash the filtrate with a small quantity of ethanol and dryto give D-(threo)-1-p-methylsulfonylphenyl-2-phthalimido-1,3-propanediol(yield=35 gms.).

To obtain additional product, evaporate the combined ethanol filtratesin vacuo, dissolve the resultant residue in ethyl acetate, wash theethyl acetate solution with 5% aqueous sodium bicarbonate, dry the ethylacetate over sodium sulfate, then evaporate in vacuo. Triturate theresultant residue with ethanol, and filter to obtain additionalD-(threo)-1-p-methylsulfonylphenyl-2-phthalimido-1,3-propanediol(additional yield=7.3 gms.); m.p. 209°-211° C.; Mass Spectrum m/e 190(Pht N═CHCH₂ OH), 186 (CH₃ SO₂ C₆ H₅ CH₂ OH).

B. D-(Threo)-1-p-Methylsulfonylphenyl-2-Phthalimido-3-Fluoro-1-Propanol

Add diethylamine sulfurtrifluoride (25 ml.) dropwise to a stirredsuspension ofD-(threo)-1p-methylsulfonylphenyl-2-phthalimido-1,3-propanediol (66gms., 0.176 mmol) in tetrahydrofuran (750 ml.) maintained at 0° C. withexternal cooling. After the addition is complete, stir for 30 minutes at0° C. and then for 6 hours at room temperature. Set aside in therefrigerator overnight. Remove the solvent by evaporation in vacuo andchromatograph the resultant residue on a silica gel column (4 kg.)eluting with chloroform:ethanol (99:1). Combine the like fractionscontaining the desired product as determined by thin layerchromatography, and evaporate the combined fractions in vacuo to aresidue ofD-(threo)-1-p-methylsulfonylphenyl-2-phthalimido-3-fluoro-1-propanol,yield 24 gms.; m.p. 166°-168° C.; Mass Spectrum: m/e 192 (Pht N═CHCH₂F), 186 (CH₃ SO₂ C₆ H₅ CH₂ OH); pmr: (dmso-d₆), δ 7.6-8.3 (aromatichydrogens); 6.1 (d, J=4.0 Hz, benzylic OH); 3.95-5.4 (m, H-1, H-2 andCH₂ F); 3.23 (s, SO₂ CH₃).

C. D-(Threo)-1-p-Methylsulfonylphenyl-2-Amino-3-Fluoro-1-Propanol

Add hydrazine hydrate (99%, 0.16 gms.) to a solution ofD-(threo)-1-p-methylsulfonylphenyl-2-phthalimido-3-fluoro-1-propanol(1.14 gms., 3 mmol) in ethanol (20 ml.). Heat at reflux temperature for4 hours, cool to room temperature and remove the resultant solids byfraction. Evaporate the filtrate to a residue comprisingD-(threo)-1-p-methylsulfonylphenyl-2-amino-3-fluoro-1-propanol.

D.D-(Threo)-1-p-Methylsulfonylphenyl-2-Dichloroacetamido-3-Fluoro-1-Propanol

Dissolve theD-(thero)-1-p-methylsulfonylphenyl-2-amino-3-fluoro-1-propanol preparedin Example 6C in methanol (5 ml.) and add methyl dichloroacetate (1gm.). Heat the reaction mixture at reflux temperature for 2 hours,remove the solvents by evaporation in vacuo and extract the resultantresidue with a mixture of chloroform:ethanol (75:25) (100 ml.).Evaporate the organic solvent extracts in vacuo and chromatograph theresultant residue on a silica gel column (90 gms.) eluting with amixture of chloroform:ethanol (93:7). Combine the like eluatescontaining the desired product as determined by thin layerchromatography and evaporate in vacuo to a residue ofD-(threo)-1-p-methylsulfonylphenyl-2-dichloroacetamido-3-fluoro-1-propanol,yield 0.5 gms.; m.p. 153°-154° C.; Mass Spectrum: M⁺ 358 pmr: (dmso-d₆)δ 8.3 (d, J=8.0 Hz, NH); 7.18-7.75 (aromatic hydrogens); 6.43 (s,COCHCl₂); 6.07 (d, J=4.0 Hz, benzylic OH); 3.9-5.1 (m, H-1, H-2 and CH₂F); 3.14 (s, SO₂ CH₃).

EXAMPLE 7D-(Threo)-1-p-Methylsulfonylphenyl-2-Difluoroacetamido-3-Fluoro-1-Propanol

Dissolve theD-(threo)-1-p-methylsulfonylphenyl-2-amino-3-fluoro-1-propanol preparedin Example 6C in ethanol (5 ml.) and add ethyl difluoroacetate (1 gm.).Heat the reaction mixture at reflux temperature for 2 hours, remove thesolvents by evaporation in vacuo and extract the resultant residue witha mixture of chloroform:ethanol (75:25, 100 ml.). Evaporate the combinedextracts in vacuo and chromatograph the resultant residue on silica gel(90 gms.) eluting with a mixture of chloroform:ethanol (93:7). Combinethe like fractions containing the desired product as determined by thinlayer chromatography and evaporate in vacuo to obtainD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanol,m.p. 141°-142° C.; Mass Spectrum: (M⁺ +1) 326; pmr (dmso-d₆) δ 8.88 (d,J=8.0 Hz, NH); 7.5-8.1 (aromatic hydrogens); 6.2 (t, J=54 Hz, COCHF₂);6.07 (d, J=4.0 Hz, benzylic OH); 3.7-5.1 (m, H-1, H-2 and CH₂ F); 3.2(s, SO₂ CH₃).

EXAMPLE 8 OtherD-(Thero)-1-p-Methylsulfonylphenyl-2-Acylamido-3-Fluoro-1-Propanols

A. In a manner similar to that described in Example 6D, treatD-(threo)-1-p-methylsulfonylphenyl-2-amino-3-fluoro-1-propanol inmethanol with methyl trifluoroacetate, and with each of the acetic acidand propionic acid ester starting compounds of Example 5A. Isolate andpurify each of the resulting products in a manner similar to thatdescribed to obtain, respectively,

D-(threo)-1-p-methylsulfonylphenyl-2-trifluoroacetamido-3-fluoro-1-propanol

D-(threo)-1-p-methylsulfonylphenyl-2-trichloroacetamido-3-fluoro-1-propanol

D-(threo)-1-p-methylsulfonylphenyl-2-dibromoacetamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-dichlorofluoroacetamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-α,α-difluoropropionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-α,α-dichloropropionamido-3-fluoro-1-propanol,and

D-(threo)-1-p-methylsulfonylphenyl-2-chlorodifluoroacetamido-3-fluoro-1-propanol.

B. In a manner similar to that described in Example 4 (method B), treatD-(threo)-1-p-methylsulfonylphenyl-2-amino-3-fluoro-1-propanol inmethanol or ethanol with each of the acetic acid and propionic acidchloride starting compounds of Example 5B. Isolate and purify each ofthe resulting products in a manner similar to that described to obtain,respectively,

D-(threo)-1-p-methylsulfonylphenyl-2-fluoroacetamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-chloroacetamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-bromoacetamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-iodoacetamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-propionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-α-fluoropropionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-α-chloropropionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-α-bromopropionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-α-iodopropionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-β-chloropripionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-β-bromopropionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-β-iodopropionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-α,β-dichloropropionamido-3-fluoro-1-propanol,

D-(threo)-1-p-methylsulfonylphenyl-2-α,β-difluoropionamido-3-fluoro-1-propanol.

EXAMPLE 9D-(Threo)-1-p-Methylthiophenyl-2-Dichloroacetamido-3-Fluoro-1-Propanol

A. D-(Threo)-1-p-Aminophenyl-2-Phthalmido-3-Fluoro-1-Propanol

Dissolve a solution ofD-(threo)-1-p-nitrophenyl-2-phthalimido-3-fluoro-1-propanol (11 gms., 32mmol) in a solution of dioxane (120 ml.) isopropanol (60 ml.) and water(10 ml.) in a 500 ml. hydrogenation flask. Add 10% palladium-on-charcoal(1 gm.) and concentrated hydrochloric acid (3 ml.) and hydrogenate at 50psi. Monitor the hydrogenation until all the starting material isconverted to the corresponding p-aminophenyl derivative (R_(f) =0.49,silica gel thin layer chromatography, dichloromethane:acetone (90:10)).Remove the catalyst by filtration and wash the catalyst with isopropanol(20 ml.). Concentrate the combined filtrate and isopropanol washings invacuo, and dissolve the resultant residue in 1 molar sodium hydroxide(30 ml.). Extract the aqueous solution several times withdichloromethane, dry the combined extracts over anhydrous magnesiumsulfate and concentrate. Crystallize the resultant residue fromanhydrous ethanol:diethyl ether and filter and dry the resultantprecipitate to obtainD-(threo)-1-p-aminophenyl-2-phthalimido-3-fluoro-1-propanol, yield=6.2gms. (19.7 mmol, 62% theory); m.p. 145.5°-147° C.; mass spectrum: M⁺314; Analysis Calculated for: C₁₇ H₁₅ O₃ N₂ F: C, 64.97; H, 4.81; N,8.91; F, 6.05. Found: C, 65.23; H, 4.96; N, 8.79; F, 5.75.

B. D-(Threo)-1-p-Methylthiophenyl-2-Phthalimido-3-Fluoro-1-Propanol

To a solution ofD-(threo)-1-p-aminophenyl-2-phthalimido-3-fluoro-1-propanol (3 gms., 9.6mmol) in methylene chloride (60 ml.) cooled to 0° C., add a solution ofnitrosyl chloride in methylene chloride (11 ml., 70 mg. per ml.). Stirat 0° C. for 20 minutes. Add sodium thiomethylate (0.8 gms.) and ethanol(10 ml.) and stir at room temperature for 18 hours. Add additionalsodium thiomethylene (0.2 gms.) and stir for one hour. Filter thereaction mixture and evaporate the filtrate to a residue comprisingD-(threo)-1-p-methylthiophenyl-2-phthalimido-3-fluoro-1-propanol, whichis used without further purification in the procedure of Example 9C.

C. D-(Threo)-1-p-Methylthiophenyl-2-Amino-3-Fluoro-1-Propanol

Dissolve theD-(threo)-1-p-methylthiophenyl-2-phthalimido-3-fluoro-1-propanolprepared in Example 9B in absolute ethanol (20 ml.) and add hydrazinehydrate (0.55 ml.). Heat at reflux temperature for 3 hours, then filter.

The filtrate containingD-(threo)-1-p-methylthiophenyl-2-amino-3-fluoro-1-propanol is usedwithout further purification in the procedure of following Example 9D.

D.D-(Threo)-1-p-Methylthiophenyl-2-Dichloroacetamido-3-Fluoro-1-Propanol

Add methyl dichloroacetate (1.4 ml.) to the filtrate containingD-(threo)-1-p-methylthiophenyl-2-amino-3-fluoro-1-propanol prepared inExample 9C. Heat the raction mixture at reflux temperature for 2 hours,evaporate in vacuo and chromatograph the resultant residue on a silicagel column (90 gms.) eluting with methylenechloride:2-propanol:concentrated ammonium hydroxide (28%) (90:6:0.1).Combine the like fractions containing the desired product as determinedby thin layer chromatography and evaporate the combined like eluates toa residue ofD-(threo)-1-p-methylthiophenyl-2-dichloroacetamido-3-fluoro-1-propanol,yield=1.1 gm.; mass spectrum: M⁺ 325, 153 (CH₃ SC₆ H₄ CH₂ OH).

EXAMPLE 10 D-(Threo)-1-Phenyl-2-Dichloroacetamido-3-Fluoro-1-Propanol

A. D-(Threo)-1-Phenyl-2-Phthalimido-3-Fluoro-1-Propanol

To a solution ofD-(threo)-1-p-aminophenyl-2-phthalimido-3-fluoro-1-propanol (800 mg.) inmethyl chloride (40 ml.) cooled to 0° C., add a solution of nitrosylchloride in methylene chloride (3 ml., 70 mg. per ml.). Stir at 0° C.for 20 minutes, then separate the resultant precipitate by filtrationand wash with methylene chloride to obtain the diazonium chloride saltfrom D-(threo)-1-p-aminophenyl-2-phthalimido-3-fluoro-1-propanol.

Dissolve the foregoing diazonium chloride salt in cold water (6 ml.) andquickly add the solution to 50% aqueous hypophosphorous acid (1.6 gms.)which has been previously cooled in a water bath. Allow the reactionmixture to warm to 25° C., then stir for 3 hours at 25° C. Extract thereaction mixture with methylene chloride (a total of 75 ml.), wash thecombined methylene chloride extracts with dilute aqueous sodiumbicarbonate, dry the methylene chloride solution over anhydrousmagnesium sulfate, and evaporate to a residue comprisingD-(threo)-1-phenyl-2-phthalimido-3-fluoro-1-propanol (yield 0.7 gms.),which is used without further purification in the procedure of Example10B.

B. D-(Threo)-1-Phenyl-2-Amino-3-Fluoro-1-Propanol

Dissolve the D-(threo)-1-phenyl-2-phthalimido-3-fluoro-1-propanolprepared in Example 10A in absolute ethanol (10 ml.), add hydrazinehydrate (0.12 ml.) and heat at reflux temperature for 3 hours, thenfilter, and evaporate the filtrate to a residue comprisingD-(threo)-1-phenyl-2-amino-3-fluoro-1-propanol, which is used withoutfurther purification in the procedure of following Example 10C.

C. D-(Threo)-1-Phenyl-2-Dichloroacetamido-3-Fluoro-1-Propanol

Dissolve the D-(threo)-1-phenyl-2-amino-3-fluoro-1-propanol prepared inExample 10B in methanol (6 ml.), add methyl dichloroacetate (14 ml.),and heat at reflux temperature, keeping the reaction mixture at pH 8 bythe addition of triethylamine. Continue refluxing until all the startingmaterial has been consumed as evidenced by thin layer chromatography onsilica gel using chloroform:ethanol (97:3) as solvent, then concentratethe reaction mixture. Purify the resultant residue by chromatography ona silica gel column (2.8×30 cm.) eluting with chloroform:ethanol (99:1),taking 4 ml. fractions, 2 minutes per tube. Combine the like fractionscontaining the desired product as determined by thin layerchromatography and evaporate to a residue comprisingD-(threo)-1-phenyl-2-dichloroacetamido-3-fluoro-1-propanol (yield 0.4gms.) (1.43 mmol, 56% theory). Mass Spectrum: 280 (M⁺ +1); 282 (M⁺ +3);107 (HO═CH--phenyl); pmr: (dmso-d₆) δ 5.86 (benzylic OH); 6.51 (Cl₂CH--); 7.31 (phenyl).

EXAMPLE 11D-(Threo)-1-p-Methylsulfinylphenyl-2-Dichloroacetamido-3-Fluoro-1-Propanol

To a solution ofD-(threo)-1-p-methylthiophenyl-2-dichloroacetamido-3-fluoro-1-propanol(compound of Example 9) (910 mg., 2.8 mmol) in 95% dioxane (10 ml.) at0° C., add sodium metaperiodate (600 mg.) and stir for 30 minutes.Destroy any excess sodium metaperiodate by addition of ethylene glycoluntil the reaction mixture is negative to starch-iodide paper. Adddioxide (twice the volume of the reaction mixture) and filter theresultant precipitated salts. Evaporate the dioxane filtrate and to theresultant residue add chloroform:ethanol (3:1, 50 ml.), then filter theresultant solid, and wash with chloroform:ethanol (3:1). Combine thefiltrate and washings, evaporate and chromatograph the resultant residueon a 15 gm. silica gel column (1.8×30 ml.) eluting withchloroform:ethanol (99:1). Combine the like fractions containing thedesired product as determined by thin layer chromatography and evaporateto a residue comprisingD-(threo)-1-p-methylsulfinylphenyl-2-dichloroacetamido-3-fluoro-1-propanol(yield 247 mg.). Mass Spectrum: 342 (M⁺ +1); 344 (M⁺ +3); 169 (HO═CHC₆H₄ SOCH₃). pmr: (dmso-d₆) δ 5.98 (d, J=3.0 Hz, benzylic OH); 6.45 (s,Cl₂ CHCO--); 7.58 (s, aromatic); 2.67 (s, CH₃ SO₂).

EXAMPLE 12D-(Threo)-1-p-Nitrophenyl-2-(R,S-Chlorofluoroacetamido)-3-Fluoro-1-Propanol

Add triethylamine (0.2 ml.) to a solution ofD-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol (prepared asdescribed in Example 1C) (1.1 gm.) and ethyl chlorofluoroacetate (0.5ml.) in ethanol (14 ml.). Heat at reflux temperature under a blanket ofnitrogen for 2 hours. Add an additional amount of ethylchlorofluoroacetate (0.5 ml.) and continue heating until the reaction isessentially complete as indicated by the absence of starting compound asdetermined by thin layer chromatography using a mixture of chloroformand methanol (9:1 by volume) as the solvent system. Evaporate thesolvents in vacuo and chromatograph the resultant residue on silica gel(40 gms.) using chloroform as the eluant. Collect like fractionscontaining the desired product as determined by thin layerchromatography, evaporate to dryness in vacuo to obtainD-(threo)-1-p-nitrophenyl-2-(R,S-chlorofluoroacetamido)-3-fluoro-1-propanol(yield 0.97 gm.). Mass Spectrum: M⁺ 309, m/e 157, 156, 153, 152, 139,137, 136, 122, 106, 105, 102, 94, 78, 77, 76, 70, 67, 62, 60, 52, 51 and50.

EXAMPLE 13D-(Threo)-1-p-Nitrophenyl-2-Dichlorodeuterioacetamido-3-Fluoro-1-Propanol

Add triethylamine (0.7 ml.) to a stirred solution ofD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol (0.75gm.) in methyl alcohol-d (i.e., CH₃ OD) (7 ml.) and stir the solution atroom temperature for 18 hours. Concentrate in vacuo and dry theresultant residue in vacuo over phosphorus pentoxide overnight. Dissolvethe residue in methanol (5 ml.) and evaporate to dryness. Repeat thisprocedure once more. Crystallize the resultant product from an ethylacetate/n-hexane mixture to obtainD-(threo)-1-p-nitrophenyl-2-dichlorodeuterioacetamido-3-fluoro-1-propanol(yield 0.59 gm.). Mass Spectrum (M⁺ +1) 326. PMR (dmso-d₆): δ8.6 (d, J=8Hz, NH), 7.96 (ABq, J=10 Hz, aromatic hydrogens), 6.15 (d, J=5 Hz,benzylic OH).

In similar manner, treat each of the products of Examples 2, (5A2),(5B12), (5B13), (5B14), (5B15), (5B19), (5B20), 6, 7, 9, 10, 11, 12 andthe 2-dihalogenoacetamido and α-halogenopropionamido products ofExamples 8A and 8B with methyl alcohol-d to obtain the respective2-dihalogenodeuterioacetamido and the 2-(α-halogenodeuteriopropionamido)derivatives.

EXAMPLE 14 SodiumD-(Threo)-1-p-Nitrophenyl-2-Dichloroacetamido-3-Fluoro-1-PropylHemi-Succinate

To D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol(1.3 gm., 4 mmols) in dioxane (12 ml.) add succinic anhydride (0.92 gm.,8 mmols) and triethylamine (2.4 ml.). Allow the solution to stand atroom temperature for 6 hours, then evaporate to a small volume anddissolve the resultant residue in chloroform (200 ml.). Wash thechloroform solution with dilute hydrochloric acid then wash with water;dry over magnesium sulfate, filter and evaporate. Recrystallize theresultant residue from diethylether to obtainD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylsuccinate;yield 950 mg. (56% theory).

DissolveD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanolsuccinate (850 mg., 2 mmols) in water, add sodium bicarbonate (168 mg.,2 mmols), stir for 15 minutes, filter, add water to the filtrate, thenevaporate to a residue comprising sodiumD-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propylhemi-succinate; yield 800 mg. PMR (D₂ O): δ2.68 (4H, m, CH₂ of thehemisuccinate), 6.1 (1H, d, J=3.0 Hz, benzylic H), 6.28 (1H, s, CHCl₂),7.8 (4H, center of AA, BB quartet, aromatic hydrogens)

EXAMPLE 15 D-(Threo)-1-p-Nitrophenyl-2-Azidoacetamido (And2-Methylsulfonylacetamido)-3-Fluoro-1-Propanols

Treat D-(threo)-1-p-nitrophenyl-2-amino-3-fluoro-1-propanol in a mannersimilar to that described in Example 2 but utilizing each of ethylazidoacetate and ethyl methylsulfonylacetate instead of ethyldifluoroacetate to obtain, respectively,D-(threo)-1-p-nitrophenyl-2-azidoacetamido-3-fluoro-1-propanol, andD-(threo)-1-p-nitrophenyl-2-methylsulfonylacetamido-3-fluoro-1-propanol,having the following physical constants: PMR (dmso-d₆): δ2.91 (3H, s,CH₃ SO₂ CH₂), 4.04 (2H, s, CH₃ SO₂ CH₂), 6.08 (1H, d, J=5.0 Hz, benzylicOH), 7.86 (4H, center of AA', BB' quartet, aromatic hydrogens).

EXAMPLE 16D-(Threo)-1-p-Nitrophenyl-2-Dichloroacetamido-3-Fluoro-1-PropanolPrepared FromD-(Threo)-2-Dichloromethyl-4-p-Nitrophenylhydroxymethyl-Δ2-oxazoline

Stir a mixture ofD-(threo)-2-dichloromethyl-4-para-nitrophenyl-hydroxymethyl-Δ²-oxazoline (1 gm.), lithium fluoride (0.5 gm.) and liquid hydrogenfluoride in a teflon-lined bomb for 24 hours. Evaporate off the gaseoushydrogen fluoride into a suitable trap, then dissolve the resultantresidue in chloroform and wash the chloroform solution twice with water,then dry over magnesium sulfate and evaporate. Chromatograph theresultant residue on silica gel using chloroform as the eluant. Collectlike fractions containing the desired product as determined by thinlayer chromatography and evaporate in vacuo to obtain a residuecomprisingD-(threo)-1-para-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol.

EXAMPLE 17D-(Threo)-1-p-Methylsulfonylphenyl-2-Difluoroacetamido-3-Fluoro-1-PropanolGlycinate Trifluoroacetic Acid Salt

DissolveD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanol(1.29 gms.), N-p-methoxybenzyloxycarbonyl glycine (1.1 gm.),N,N-dicyclohexylcarbodiimide (1.1 gm.) and pyridine (0.5 ml.) inacetonitrile (50 ml.). Stir for 4 hours, then evaporate in vacuo at 50°C. and chromatograph the resultant residue over silica gel (200 gms.)eluting with 1% ethanol/chloroform. Collect the like fractionscontaining pureD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanolN-p-methoxybenzyloxycarbonylglycinate as determined by thin layerchromatography and evaporate. Dissolve the resultant residue underanhydrous conditions in trifluoroacetic acid (20 ml.). Add ethyl ether(100 ml.) to the solution and separate the resultant precipitate byfiltration. Dissolve the precipitate in water, filter and lyophilize theaqueous solution to obtainD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanolglycinate trifluoroacetic acid salt, yield 1.23 gms.; pmr (dmso-d₆),

δ 7.84 (ABq, J=8 Hz, aromatic hydrogen),

δ 6.25 (d, J=3 Hz, H-1),

δ 6.05 (t, J=53 Hz, CH₂ F),

δ 4.07 (s, glycyl CH₂),

δ 3.17 (s, SO₂ CH₃).

EXAMPLE 18D-(Threo)-1-p-Methylsulfonylphenyl-2-Difluoroacetamido-3-Fluoro-1-PropanolOrnithate Trifluoroacetic Acid Salt

TreatD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanolin a manner similar to that described in Example 17 but usedi-N-p-methoxybenzyloxycarbonyl ornithine (2.3 gms.) instead ofp-methoxybenzyloxycarbonyl glycine to obtainD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanolornithate trifluoroacetic acid salt, yield 0.84 gms., pmr (dmso-d₆),

δ 7.87 (ABq, J=8 Hz, aromatic hydrogen),

δ 6.19 (d, J=3 Hz, H-1),

δ 6.07 (t, J=53 Hz, CH₂ F),

δ 3.2 (s, SO₂ CH₃),

δ 1.92 (broad, ornithine CH₂ --CH₂),

δ 3.0 (broad, ornithine CH).

EXAMPLE 19D-(Threo)-1-p-Methylsulfonylphenyl-2-Difluoroacetamido-3-Fluoro-1-PropanolLysinate Trifluoroacetic Acid Salt

Treat-D-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanolin a manner similar to that described in Example 17, but usedi-N-p-methoxybenzyloxycarbonyl lysine (3.06 gms.) instead ofp-methoxybenzyloxycarbonyl glycine to obtainD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanollysinate trifluoroacetic acid salt, yield 3.1 gms., pmr (dmso-d₆),

δ 7.81 (ABq, J=8 Hz, aromatic hydrogens),

δ 6.19 (d, J=3 Hz, H-1),

δ 6.08 (t, J=53 Hz, CH₂ E),

δ 3.23 (s, SO₂ CH₃),

δ 2.90 (broad, lysine CH),

δ 1.90 (broad, lysine CH₂)

EXAMPLE 20 The Sulfuric Acid Salts ofD-(Threo)-1-p-Methylsulfonylphenyl-2-Difluoroacetamido-3-Fluoro-1-PropanolGlycinate and ofD-(Threo)-1-p-Methylsulfonyl-2-Difluoroacetamido-3-Fluoro-1-PropanolOrnithate

(1) Dissolve the trifluoroacetic acid salt product of Example 17 intetrahydrofuran and add 0.5 molar equivalents of sulfuric acid.Evaporate the tetrahydrofuran in vacuo, then re-dissolve the resultantresidue in tetrahydrofuran and evaporate again. Repeat this procedureuntil all the trifluoroacetic acid is displaced by sulfuric acid asevidenced by cmr data to obtainD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanolglycinate sulfuric acid salt.

(2) Treat the trifluoroacetic acid salt of each of Examples 18 and 19 ina manner similar to that described above to obtainD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanolornithate sulfuric acid salt andD-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanollysinate sulfuric acid salt, respectively.

I claim:
 1. A D-(threo-1-aryl-2-amino-3-fluoro-1-propanol of thefollowing formula: ##STR8## wherein R₂ and R₃ are hydrogen or togetherwith the attached nitrogen form phthalimido or succinimido;each of X andX' is a member selected from the group consisting of NO₂, SO₂ R₁, SOR₁,SR₁, SONH₂, SO₂ NH₂, SONHR₁, SO₂ NHR₁, COR₁, OR₁, R₁, CN, halogen,hydrogen, phenyl, and phenyl substituted by halogen, NO₂, SO₂ CH₃, R₁ orOR₁, wherein R₁ is methyl, ethyl n-propyl or isopropyl.
 2. A compound ofclaim 1 wherein X' is hydrogen and X is NO₂, SO₂ R₁, SOR₁ or SO₂ HN₂. 3.A compound of claim 1 wherein R₂ and R₃ are hydrogen or together withthe attached nitrogen form phthalimido, X' and Z are hydrogen, and X isNO₂, SO₂ R₁, SOR₁ or SO₂ NH₂.
 4. The process for the preparation of aD-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol of the followingformula: ##STR9## wherein R is a member selected from the groupconsisting of methyl or ethyl or a halogenated derivative thereof,dihalogenodeuteriomethyl, 1-halogeno-1-deuterioethyl,1,2-dihalogeno-1-deuterioethyl, azidomethyl and methylsulfonylmethyl;each of X and X' is a member selected from the group consisting of NO₂,SO₂ R₁, SOR₁, SR₁, SONH₂, SO₂ NH₂, SONHR₁, SO₂ NHR₁, COR₁, OR₁, R₁, CN,halogen, hydrogen, phenyl and phenyl substituted by halogen, NO₂, SO₂CH₃, R₁ or OR₁, and whereinR₁ is methyl, ethyl, n-propyl or isopropyl;which comprises the reaction ofD-(threo)-1-aryl-2-N-protected-amino-1,3-propanediol with dialkylaminesulfur trifluoride in an inert organic solvent followed by removal ofthe N-protecting group in the thereby formedD-(threo)-1-aryl-2-N-protected-amino-3-fluoro-1-propanol; thencereaction of the resulting D-(threo)-1-aryl-2-amino-3-fluoro-1-propanolwith a lower alkanoic acid derivative selected from acetic acidanhydride, acetyl chloride, propionic acid anhydride or propionylchloride, a halogeno acetic acid chloride or anhydride in the presenceof base, a halogeno propionic acid chloride of anhydride in the presenceof base, or with a lower alkyl ester of an α,α-dihalogeno acetic acid orof an α,α-dihalogeno propionic acid ester in a lower alkanol.
 5. Theprocess of claim 4 wherein said dialkylamine sulfur trifluoride isdiethylamino sulfur trifluoride and wherein said lower alkyl ester of alower alkanoic acid is methyl dichloroacetate or ethyl difluoroacetateor ethyl chlorofluoroacetate whereby is prepared aD-(threo)-1-aryl-2-dichloroacetamido-3-fluoro-1-propanol,D-(threo)-1-aryl-2-difluoroacetamido-3-fluoro-1-propanol, or aD-(threo)-1-aryl-2-chlorofluoroacetamido-3-fluoro-1-propanol,respectively.
 6. The process of claim 4 wherein saidD-(threo)-1-aryl-2-N-protected-amino-1,3-propanediol isD-(threo)-1-p-nitro-phenyl-2-phthalimido-1,3-propanediol, saiddialkylamine sulfur trifluoride is diethylamine sulfur trifluoride,wherein said lower alkyl ester of an alkanoic acid is methyldichloroacetate, ethyl difluoroacetate or ethyl chlorofluoroacetate,whereby is formed, respectively,D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-3-fluoro-1-propanol,D-(threo)-1-p-nitrophenyl-2-difluoroacetamido-3-fluoro-1-propanol, andD-(threo)-1-p-nitrophenyl-2-fluorochloroacetamido-3-fluoro-1-propanol.7. The process of claim 4 wherein saidD-(threo)-1-aryl-2-N-protected-amino-1,3-propanediol isD-(threo)-1-p-methylsulfonylphenyl-2-phthalimido-1,3-propanediol, saiddiethylamine sulfur trifluoride is diethylamine sulfur trifluoride andsaid lower alkyl ester of a lower alkanoic acid is methyldichloroacetate, ethyl difluoroacetate, or ethyl chlorofluoroacetate,whereby is formed, respectively,D-(threo)-1-p-methylsulfonylphenyl-2-dichloroacetamido-3-fluoro-1-propanol,D-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-3-fluoro-1-propanol,andD-(threo)-1-p-methylsulfonylphenyl-2-fluorochloroacetamido-3-fluoro-1-propanol.